The modification of pharmaceutical and biologically active compounds to alter or enhance their functional properties is known in the art. Typically, prior art efforts have been directed to the production of carrier-bound drugs in which carrier molecules having selective physical properties, such as enhanced water solubility, are chemically attached to biologically active compounds. For example, Jacobson and colleagues have developed what is referred to as the "functional congener" approach to the design of carrier-bound drugs (Jacobson, K. A., in Adenosine Receptors; Cooper, D. M. F., Londos, C., Eds., Receptor Biochemistry and Methodology; Venter, J. C., Harrison, L. C., Eds., Alan, R., Liss: New York, 1988, Vol. 11, pp. 1-26). This approach involved the modification of well-defined drug molecules at non-sensitive positions in a manner that retained the drug's ability to bind at its specific receptor site. In order to produce a chemically functionalized drug congener, they modified the drug molecule by the introduction of a chemical functional group which could then be covalently attached to a carrier molecule. This produced a bifunctional molecule in which one portion (the "pharmacophore") contributed its biological activity, and the second portion, or carrier, imparted its selective physical properties such as enhanced receptor attachment or water solubility. Using this approach, functional congener compounds were prepared using catecholamines, adenosine receptor agonists and antagonists, and muscarinic agents.
However, recent developments in the understanding of biological mechanisms such as the binding of selective ligands to receptors and their related functions and such seemingly diverse physiological systems as the cardiovascular system, the central nervous system, and the immune system has stimulated efforts to discover alternative methods for designing biologically active compounds exhibiting properties which will selectively treat or regulate such seemingly diverse physiological systems without serious or disabling side effects that might otherwise occur. For example, adenosine receptors have been found in the cardiovascular system, the central nervous system, and the immune system. Accordingly, it was originally believed that the development of adenosine analogues would be effective in regulating or modifying the biological activities associated therewith. However, the ubiquitous distribution of adenosine receptors has resulted in the production of serious and disabling side effects in what were originally believed to be unrelated biological systems, thereby significantly reducing the therapeutic usefulness of adenosine analogues.
Similar interrelationships have also been discovered to exist between the mammalian immune system and the mammalian nervous system. Over the past several decades numerous researchers have added considerable detail to the overall understanding of the mammalian immune system and its importance in maintaining overall physical health. In more recent years, similar detail has evolved in the study of the nervous system. As more and more information was developed in the seemingly independent fields of study, a number of close functional parallels began to appear between the two physiological systems. For example, both systems are concerned with the storage of information and use soluble chemicals to transmit signals between cells. Additionally, natural endogenous substances, such as hormones and transmitters, are active on the cells of both systems. Even more significantly, some common functions between the two systems are based upon similar chemical structures or markers on the surfaces of both nerve cells and immune cells. The recent discovery that the CD4 receptors targeted by the AIDS virus are present on both the T4 lymphocyte and on neurons is one of the more dramatic examples of the close relationship between the nervous system and the immune system.
Further crossing the classically imposed barriers between the fields of immunology and neurology, recent developments in the understanding of Alzheimer's disease have implicated an immunologic component that may be present in this neurological disorder. It has been proposed that both the anatomical and biochemical specificity of the defects seen in Alzheimer's disease could be explained by an immunologic attack on the brain blood vessels themselves with secondary involvement of neuronal, glial, or synaptic constituents contributing to the formation of senile plaques, or an immune-mediated compromise of vessels associated with an immune attack on specific neuronal, glial, or synaptic constituents (Appel, S. H., Neurobiol. Aging, 7:512, 1986).
Additionally, circumstantial evidence for any immunological component in neurologic disorders is also provided by the altered suppressor cell function and aging populations, and more specifically in Alzheimer's disease (MacDonald et al., Clin. Exp. Immunol. 49:123-8, 1982; Miller, A. E., Ann. Neurol. 10:506-10, 1981; Stefansson, K. in Clinical Neurology of Aging, Ed. M. L. Albert, Oxford Univ. Press, 1984, pp. 76-94), the implication of HLA regions of chromosome 6 and the GM locus chromosome 14 in a large kindred with Alzheimer's disease (Weitkamp, L. R., Am. J. Hum. Genet. 35:443-53, 1983) and by the altered immunological parameters in Down's syndrome, a disease whose symptoms are similar to senile dementia of the Alzheimer's type (SDAT).
Scientists in the nascent field of neuroimmunology have hypothesized the effects and the function of brain cells (neurons) may be observed concomitantly as parallel defects or deficiencies in receptors on the cells of the immune system (such as peripheral blood immune cells). The validity of this hypothesis was recently brought to light with the aforementioned discovery of HIV infection in neurons. This neuroimmunologic theory has had significant impact because formerly almost all neuropsychiatric disorders were thought to be primarily due to factors such as genetic predisposition, mental attitude, and/or resistance to natural environment rather than defects or deficiencies in cell function. Similarly, though the immune system has been implicated in numerous diseases resulting from infection and cancer to degenerate diseases such as Alzheimer's disease, arthritis and aging, its relationship to cognitive functioning was previously unrealized.
Because the chemical interrelationship between these diverse physiological systems has been recognized only recently, prior art medical treatments and pharmaceutical agents have focused almost exclusively on treating the individual systems alone. Thus, pharmaceutical compounds have been developed for treating or regulating the cardiovascular system or the immune system or the central nervous system with the idea of avoiding undesirable interactions in what are now known to be related physiological systems. By far the greatest amount of recent effort in the pharmaceutical and medical fields has been devoted to the treatment and regulation of the immune system alone. Numerous immunomodulating and antiviral agents have been disclosed in the art such as those described in European Patent Application Publication No. 0126813 (Simon et al.), U.S. Pat. No. 4,221,909 (Simon et al.), U.S. Pat. No. 4, 211, 794 (Kraska), and U.S. Pat. No. 4,221,910 (Giner-Sorolla). Unlike antibiotics which directly attack or destroy invading organisms such as bacteria, immunomodulating agents and more specifically immune enhancing agents are compounds which help to bolster the body's own defense mechanisms against the effects of infections. Immunomodulators either restore depressed immune function, or suppress hyperactive immune function.
Though the AIDS epidemic has focused considerable resources and attention to the study of defects and deficiencies in the immune system, outside of the recent discovery of HIV infection in neural tissue, comparatively little research has been directed to the development of multifunctional pharmaceutical compounds such as neuroimmunologic agents or other compounds exhibiting functionally related and mutually supportive therapeutic activities such as immunomodulating with cardiovascularly active compounds or immunomodulating with antimicrobially active compounds.
One of the aspects of neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Parkinson's disease, and other similar diseases and conditions is the occurrence of the death of nerve cells, particularly motor neurons. Similar death occurs after injuries such as spinal cord injuries. More than 100, 000 Americans are estimated to sustain spinal cord injuries each year. The final outcomes of these injuries are not only determined by the mechanical trauma but also by the subsequent cellular and molecular events which constitute the secondary injury. Conventional therapy is generally aimed at reducing the initial inflammatory response and edema to lessen secondary damage. More recently, physicians and researchers have strived to promote regeneration of severed connections.
Neurotrophic factors have been shown to play a role in the regeneration of spinal cord motor neurons in vitro (V. M. K. Verge et al., Phil. Trans. Roy. Soc. B. 351: 423-430 (1996)). Although attempts have been made to reverse this cell death and promote regeneration of motor neurons by the administration of nerve growth factors, such efforts are complicated by the existence of the blood-brain barrier. The difficulty in the use of neurotrophic factors themselves as therapeutic agents lies in the delivery of the large protein molecules to the spinal cord. Oral delivery is not possible for proteins owing to the activity of proteases in the digestive tract and neurotrophic factors are too large to pass through the blood-brain barrier after injection. Clinical trials with one neurotrophic factor, CNTF, demonstrated the significant side effects associated with systemic delivery (ALS CNTF Treatment Study Group, Neurology 46: 1244-1249 (1996)).
A novel approach to neurotrophic factor therapy involves transplanting cells transfected with neurotrophic factor genes directly into the spinal cord lesion. This approach also has several drawbacks. Generally, each group of transplanted cells produces only one neurotrophic factor and studies to date suggest that a combination of factors may be required for a successful regenerative response (R. Grill et al., J. Neurosci. 17: 5560-5572 (1997)). In addition, this is an invasive treatment which may present adverse responses including inflammatory responses, localized hyperplasia, and uncertain levels of neurotrophic factor production. Similar and additional concerns arise with delivery of neurotrophic factors directly into the cerebrospinal fluid (E. F. Fernandez et al., Neurosurgery 33: 889-893 (1993)). A small orally-absorbed molecule, which passes the blood-brain barrier and which stimulates the appropriate neurotrophic factor production at the required location, would be preferable.
Therefore, there is a requirement for improved methods of administering compounds that can stimulate the activity of nerve growth factors and enable the regeneration of motor neurons to restore functioning of the central nervous system in such conditions. There is a particular need to do so using compounds and compositions that selectively pass through the blood-brain barrier.
Accordingly, it is a principal object of the present invention to disclose multifunctional pharmaceutical compounds possessing at least two separate pharmacological activities that are functionally related and mutually supportive therapeutically.
It is an additional object of the present invention to provide multifunctional pharmaceutical compounds pairing biologically active chemical moieties such as immunomodulating pharmacophores, neurological pharmacophores, cardiovascular pharmacophores and anti-microbial pharmacophores as well as others.
It is a further object of the present invention to provide multifunctional pharmaceutical compounds combining biologically active chemical moieties which produce a combined pharmacological activity differing in either or both quantity or character from the individual pharmacological actions of the separate chemical moieties. It is a further additional object of the present invention to disclose specific neurologically active immunomodulating compounds that are pharmaceutically active with respect to defects or deficiencies, into both the central nervous system and the immune system. These particular compounds will be especially effective for treating neuroimmunologic conditions such as Alzheimer's disease, AIDS, disorders of memory, and disorders of immune function, as well as the effects of aging.
It is a further object of the invention to provide improved methods for stimulating nerve growth in neurodegenerative conditions such as Alzheimer's disease, ALS Parkinson's disease and other similar conditions by using reagents that selectively pass through the bloodbrain barrier.